1-(p-halobenzyl)-2-methyl benzimidazoles and salts



2,875,233 ICC, tea Mar- .3, 1959 1-(p-HALOBENZYL)-2-METHYL BENZIMIDAZQLES AND SALTS Siegfried Herrling and Herbert Keller, Stolberg, Rhineland, and Heinrich Miickter, Aachen, Germany, assignors-to. Chemie Gruenenthal G. m. b. H., Stolberg, Rhineland,. Germany, a corporation of Germany No Drawing. Application October 29, 1956 r Serial No. 619,086

7 01mm. c1. zen-309.2

when the l-position is occupied by a substituted or=unsubstituted aralkyl, aryl, or heterocyclic residue or, respectively, by a heterocyclically substituted alkyl residue.

Derivatives of benzimidazole have been suggested for the treatment of fungus'infections of; the human or animal body.- However, such compounds have not proved to be satisfactory.

zole derivatives is given in the following Table II. The

It is one object of the present invention to provide new and valuable derivatives of benzimidazole and salts of such compounds which have a high spasmolytic activity and are also highly elfective fungistatic agents.

A further object of the present invention is to p ovide new and valuable therapeutically useful compositions .Such benzimidazole derivatives and their acid addition salts possess valuable therapeutic activity.

The new benzimidazole compounds correspond to the following formula 4 In said formula X indicates an alkyl radical containing 1 to 4 carbon atoms which may be substituted by hydroxyl group, especially the methyl radical and the hy droxy methyl group; Y' indicates halogen, especially chlorine; R R R R, indicate hydrogen, lower alkyl pounds may also be substituted, for instance, by lower alkyl radicals, halogen, nitro groups, or amino groups.

radicals, halogen, nitro groups, or amino groups which J may be substituted.

The new compounds are capable of forming salts with acids due to the basicity of the imidazole nucleus.

'Ihenew benzimidazole derivatives have valuable spasmolytic properties. They are highly effective fungistatic agents. 3

The superior spasmolytic activity of the new benzimidazole derivatives follows from comparative tests whereing their action upon contractions of the guinea pig intestines caused by the action of acetyl choline or barium chloride was compared with that of papaverine. The tests were carried out according'to the method described by Magnus. The values obtained in such tests are given in the followirig-Table I.

. TABLE I I Thesuperior fungistatic activity of the new benzimidafungistatic activity was determined according to the progres'sive dilution test whereby Sabourauds agar was used and the cultures were incubated at 24 C. for 14 days.

In said table compound I is the known l-p-chloro benzyl benzimidazole, compound II is l-p-chloro benzyl-Z-methyl benzimidazole of Example '1 given hereinafter.

TABLE II Threshold Concentrations of Fungistatlc Activity Compound Epldermoy Triclgaphyton 'Sporotrichum phyton mter- Candzda Kaufimann- Beurmann digitale albzcans Wolfl The new valuablederivatives of benzimidazoleare prepared according to methods known per se. For instance, o-phenylene diamine substituted in the l-amino group by a p-halogeno benzyl residue which may also be substituted in the benzene nucleus by the substituents R R R R is reacted with a compound of the formula R-X, wherein R indicates a group adapted for ring closure to form the benzimidazole ring while X indicates an alkyl 1 radical with l to 4 carbon atoms which may be substituted by hydroxyl groups.

It is also possible to convert a Schilfs base of the formula wherein X, Y, R R R and R represent the same substituents as indicated hereinabove, into the correspond tion to render it weakly alkaline.

ing benzimidazole compound by oxidation. Such reactions are. carried out, im ins ances 1. 1.2116, manner as described by Hinsberg, Ben, vol. 20 (1887), page 1565; Hinsberg and Keller, Ber,." vol. 29 (1896), page 1497; Fischer, Ben, vol. 26 (1893), page 203; Jacobson, Jenicke, and Meyer, Ben, vol. 29 (1896), page 2682; Weidenhagen, Ben, vol. 69 (1936), page 2263; Weidenhagen and Train, Ben, vol. 75 (1942), page 1936; Stevens and Bower, J. Chem. 506., vol. 1949 page 2971, and vol. 1950, page 1722; Jerchel, Fischer, and .Kracht, Ann. Chem, vol 575 (1952), page 162; Jerchel, Kracht and Krucker, fAnn. Chem." vol. 599 (1955), page 23.2.

Another method of producing the new benzimida zole derivatives consists in meeting a b nzitn daz le om oun which is substituted. n 2-p sit on by th su i n .X and which may be substituted in the benzene nucleus by the substituents R R R and R or the metal compounds of such benzimidazole compounds with a halogeno benzyl halo-genide.

According to a further method of preparing the new benzirnidazole derivatives, an N-(p-halogeno benzyl)-onitro aniline which may be substituted in the benzene nucleus by the substituents R R R and R is acylated by means of a compound of the formula R-X, wherein .R indicates a group suitable for acylation, while X represents the above indicated substituent. The nitro group is then reduced to the amino group and imidazole ring closure is effected.

.salt of the new "benzirnidazole derivative by metathesis.

The following examples-serves to illustrate the present invention without, however, 'limiting the same thereto.

Example 1 26.4 g. of Z-methyl benzimidazole are dissolved in 350 ..cc. .of dioxane. g. ofsodiumam a added thereto. After about 5 minutes 412 g. of p-chloro benzyl bromide .are added .to the resulting mixture which is then boiled under reflux for 6 hours. Dioxane is removed by distillation. The residue vis triturated with dilute hydrochloric acid. The resulting crystalline mass .Z-methyl benzimidazole is filtered off by suction and recrystallized from water. On cooling, colorless crystals are obtained which are dissolved in hot water. Dilute ammonia solution is added to the resulting aqueous solu- The base of 1-pchloro-benzyl-Z-methyl benzimidazole precipitates, first ,in liquid form, .and gradually solidifies to a whitemass of its hydrate which, after recyrstallization from aqueous ethanol, has a melting point of 67-68 ,C. The reaction mixture may also be worked up by removing dioxane by distillation and distilling the resulting residue in ,a vacuum. The base .of l-p-chloro'benzyl-Z-methyl benzimidazole ,distills in the form of a colorless oil at 240242 C./ 12 mm. Its hydrate of the;melting point :67.6.8 C. is Obtained by trituration with water.

By proceeding in the same manner as describedhere inabove, the following l-p-chloro benzyl benzimidazole compounds areobtained:

From 2-ethyl benzimidazole: l p-chl-oro benzyl-Z-ethyl benzimidazole of the melting.point 1l6ll8 C. From 2-n-propyl benzimidazole: 1-p-chloro benzyl-Z- propyl benzimidazole of the melting point 115-116 C. From 2-(isobutyl) benzimidazole: l-p-chloro benzyl- (isobutyl) benzimidazole, the hydrochloride of which 1 .has'a: mel ting;point;of,,240,C.

Example 2 Example 3 12.0 g. of potassium hydroxide are added to the solution of 26.4 g. of Z-methyl benzimidazole in 200 CC.'Of dimethyl formamide. The mixture is boiled under reflux for 10 to 15 minutes, whereby the potassium hydroxide is completely dissolved. "Asolution of 20.6 g. of p-chloro benzyl bromide in 50 cc. of dimethyl formamide is then added to the resulting solution and the mixture is heated to boiling under reflux for 2 hours. The residue obtained after distilling off the dimcthyl forrnamide is worked up as described hereina'oove in Example 1 and yields the same l-p-chloro benzyl methyl 'benzimidazole.

Example 4 23.3 g. of p-chloro benzylso-phenylene diamine are boiled under reflux with ,cc. of glacial acetic acid for 3 hours. Most of the acetic acid is then removed by distillation, Dilute sodium hydroxide solution is added to the residue to render it Weakly alkaline. The resulting base of 1-p c hloro benzyl-Z-methyl benziznidaz.ole is purified as such by recrystallization from aqueous ethanol. It may also be converted into its hydrochloride which is then worked up as described hereinabove in Example 1.

Example '5 -50 cc. of 18% hydrochloric acid are added to 23.3 g. of p-chloro benz-yl-o-phenylene 'diamine- A mixture of 35 cc. of 36% glycolic acid solution and 22 ccfof 36% hydrochloric acidis then added thereto. The reaction mixture is boiled under reflux for 3 hours. An equal volume of water and decolorizing charcoal are added thereto; the mixture is boiled nad filtered by suction. The filtrate is rendered weakly alkaline by the addition of ammonia solution. The resulting precipitated base of l-p-chloro benzyl-2-hydroxy-methyl benzimidazole is recrystallized from aqueous ethanol. It has a melting point of 165 C.

Example 6 6.1 g. of N-acetyl-N-(p-chlo-ro benzyl) -o-nitro aniand 5 g. of iron powder for 5 hours. After cooling, the reaction mixture is diluted with water to avolume of about ZOO cc. 10 cc. of concentrated hydrochloric acid are added thereto. The hydrochloride of l-p chloro benzyl-2 rnethyl benzimidazole crystallizesjafter standing for some time. It is recrystallized from water and melts, after drying, at 2 27- -228 C.

Example 7 4 g. of N-(p-chloro'benzyD- phenylene diamine hydrochloride are dissolved in 5 cc. of 75% ethanol while heating gently. The solution is added to a cooled solution of 6 g. of copper acetate ,andlOO cc. of water to which 3.5 cc. of butyraldehyde have been added. Separation of a precipitate-.-sets thereby. The mixture is heated to -90" C. for 15 minutes and is then allowed to cool. The supernatant liquid is decanted from The precipitate is stirred .with a xture is ;heate d; to boilingan-d the copper-present mqxs. 2 menstruat n withshu tsssngu fide. The yellowish solution obtained after filtering ed the precipitated copper sulfide, is concentrated by evaporation to half its volume, filtered, while still hot, through decolorizing carbon, and rendered alkaline by the addition of sodium hydroxide solution. The precipitating product represents l-p-chloro benzyl-2-n-propy1 benzimidazole which melts, after drying, at 115-117 C.

Example 8 11 g. of 2-methyl-5,6-dinitro benzimidazole are suspended in 75 cc. of acetone. A solution of 10.3 g. of p-chloro benzyl bromide in 75cc. of acetone is added thereto. The mixture is heated to boiling while stirring. A solution of 3 g. of potassium hydroxide in 10cc. of water is then added drop by drop thereto. Subsequently 'the mixture is boiled under reflux for 5 more hourswhile stirring. Acetone is removed by distillation in a vacuum and the residue is thoroughly washed with water. The washed residue is recrystallized from water containing dimethyl formamide or from acetone. Thereby l-p-chloro benzyl-Z-methyl-S,6-dinitro benzimidazole is obtained in a yield of 79% of the theoretical yield. Its melting point is 243-244" C.

Example 9 -l-p-chloro benzyl-2-methyl-5,fi-diamino benzimidazole is obtained. If required, it is dissolved in water and converted into other salts, for instance, the nitrate or the perchlorate by the addition of the equimolecular amount of nitric acid or perchloric acid and heating the mixture to remove the acetic acid and then cooling the heated mixture.

Example 10 3 g. of 2-methyl-5,6-dichloro benzimidazole are dis solved in 100 cc. of acetone. A solution of 3.0 g. of p-chloro benzyl bromide in 50 cc. of acetone are added thereto. The mixture is heated to boiling while stirring. A solution of 1 g. of potassium hydroxide in 5 cc. of water is added drop by drop thereto. The resulting mixture is then boiled under reflux for 3 hours. The reaction mixture is filtered while still hot, and acetone is removed from the filtrate by distillation in a vacuum. The resulting residue. is recrystallized from ethanol with the addition of decolorizing charcoal. 2.8 g. of l-p-chloro benzyl-Z-methyl-5,6-dich1oro benzimidazole melting at 192-193 C. are obtained thereby. The yield is 57% of the theoretical yield.

Example 11 Other salts of l-p-chloro benzyl-Z-methyl benzimidazole than the hydrochloride disclosed in Example 1 are prepared by suspending l-p-chloro benzyl-Z-methyl benzimidazole in warm Water, adding thereto the respective acid in an equimolecular amount and cooling and, if required, concentrating by evaporation the resulting mixture whereby the respective salt of l-p-chloro benzyl-2- methyl benzimidazole crystallizes. The melting points of the following salts were determined as follows:

Salt: Melting point, C.

games (a) Hydrobromide 227-228 (I Nitrate 1 178-179 (c) Perchlorate -e .L.......' 219-221 (d) p-Sulfo'salicylate 224-227 (e) p-Toluene sulfonate 212-214 Said salts are white, crystalline compounds which are difiicultly soluble in water and rather readily soluble in alcohols.

Melting point, C. 86

(f) Sulfate (g) Phosphate These salts are rather readily soluble in water.

Example 2 In a similar manner there are obtained the acid salts of l-p-chloro benzyl-Z-methyl benzimidazole with sulfuric acid or phosphoric acid by employing molecular amounts of said benzimidazole compound and of said acids. The acid sulfate and the acid phosphate are readily soluble in water and yield aqueous solutions of the pH-value of about 3.0 to 4.0.

Example 13 Example 14 The salt of undecylenic acid with l-p-chloro' benzyl-2- methyl benzimidazole is obtained inv a similar manner as described in Example 12. It forms an oil which is soluble in 1,2-propylene glycol.

In place of Z-methyl -benzimidazole,-2-ethyl benzimidazole, Z-n-propyl benzimidazole, and- 2-(iso-butyl) benzimidazole used as starting material in Example 1, there can be employed equimolecular amounts of Z-(isopropyl) benzimidazole, 2 (n butyl) benzimidazole, 2-(secondary butyl) benzimidazole whereby the procedure is the same as described inEXample 1. The resulting l-p-chloro-benzyl-Z-(iso-propyl) benzimidazole, '1pchloro benzyl-Z-(n butyl) benzimidazole, l-p-chloro benzyl-Z-(secondary butyl) benzimidazole can also be converted into their highly fungistatic addition salts with acids.

When using p-bromo benzyl-o-phenylene diamine or p-iodo benzyl-o-phenylene diarnine in place of p-chloro benzyl-o-phenylene diarnine i i- Examples 4 and 5 and otherwise proceeding as described in said examples, l-pbromo benzyl-Z-methyl benzimidazole, l-p-iodo benzyl- Z-methyl benzimidazole, l-p-bromo benzyl-2-hydroxy methyl benzimidazole, and l-p-iodo benzyl-Z-hydroxy methyl benzimidazole are obtained,

In place of Z-methyl benzimidazole used in Examples 1 and 2, there can be employed as starting materials equimolecular amounts of 2,5-dirnethyl, 2,6-dimethyl, Z-rnethyl 6 ethyl, 2-methyl-6-chloro benzimidazole, Z-methyl-S-amino, 2-methyl-6-nitro, 2-methyl-6-dimeth-ylamino benzimidazole and the like 2-(lower)-alkyl substituted benzimidazole compounds having in the benzene ring one or more alkyl, halogen, nitro, or amino substituents. The procedure is otherwise the same as that described in the above given Examples .1 to 3. The resulting benzimidazole compounds alsoform salts with acids.

In place of the salts mentioned hereinabove, there can ,be produced salts of the new benzimidazole compounds with other acids such as inorganic acids, for instance, hydroiodic acid, or with organic acids such as oxalic acid, succinic acid, malonic acid, maleic acid, citric acid, tartaric acid, malic acid, benzoic acid; s a lic ylic acid, 'phthalic acid, nicotinic acid; furane-Z-carboxylid acid and others.

The most preferred therapeutically useful compound of this group of compounds are l-p-chloro benzyl-2- methyl benzimidazole and its acid addition salts, since the like readily spreadable preparations. The fungistatic eompouridsare worked into such cremes, ointments, and thelike bymeans of emulsifying agents and/or agents pro- .nioting their disperisibility in suchb'ases. l Aqueousfemulsions or dispersions of the new fungistatic benz'imidaz'ole,compounds'can also be employed. To pro"- dues such" emulsions -or dispersions, the benzimida'zole compound is preferablyfirst mixed with a dispersing 'or emulsifying agent, andthe' mixture is then introduced in water, while stirring vigorously or passing the mixture together with waterthrough an emulsifier. Various sur- Lface activecompounds of anionic, cationic, or non-ionic nature may be employed as emulsifying or dispersing agents, such as soaps, fatty alcohol sulfonates, higher molecular quaternary ammonium compounds, condensation products of poIyoxy ethylene with fatty acids, sorb itan stearates, palmitates, olcates, and others. is l Another mode of application'of the new fungistatic benzimidazole compoundsto infected skin areas consists in using said compounds powder form. Such powder form is of importance, for instance, in the use as prophylactic agent to prevent re-infection after a cure has been accomplished. In this form, usually higher concentrations are required than when applying the new benzimida zole compouncls in liquid form. The powders are prepared, for instance, by intimately mixing and milling the benzimidazole compound with a solid pulverulent extendingagent tothe desired degree of fineness. The particle size of-the fungistatic agent should be smaller than about 100a and preferably between about and in. As solid extending agents for such powders there are used various'inert pulverulent materials of inorganic or organic nature, such as calcium phosphate, magnesium oxide, aluminum oxide, pulverulent silica gel, powdered wood, cork,talcuin or other vegetable material.

One may add other substances to the various preparations mentioned inorder to impart thereto any desired property. Such substances are, for instance, wetting agents, .adhesive substances such as casein, glue, resins, fats, and others, dyestuffs, perfumes, dust'binding agents in the case of pulverulent preparations, and others. By selecting various extenders and additives, one may render the preparation suitable for various purposes and special conditions of application. I

The lowest reliable efiective concentration of the new benzirnidazole compounds in such preparations is of the orderof at least 0.1%. The most preferred concentration is about 1.0%. 'In aqueous emulsions, suspensions, creams, ointments, bases and the like preparations, the content of the benzimidazole compound is preferably somewhat higher and may be between about 0.5% and about 10.0%, although the invention is not limited to such values. 'Pulverulent preparations contain even higher concentrations and rna'y'contain up to 50% and even more of the newfungistatic ben'z'ir'nidazole compound.

As stated hereinabove, the new benzirnidazole compounds can use beused as spa smolytic agents in place papaverine. For such a use they are also preferably tedw h a suitable pharmaceutical carrier. As solid rrnaceutical carrier, there are employed substances which are lco yention'ally used in making tablets, pills, lozenges, dragees andfthe v ukei tps susas to be adming u y s M 925 2? en ati nal :thsssomhti c mman nil.-

.tions.

in water by means of emulsifying or suspending agents, ,for instance, syrup preparations containing said compound finelydispersed .therein, may also be prepared. The new compoundsfmay furthermore be employed in the form of powders filled into gelatine capsules or the like. The powders are obtained in the .same manner as described hereinbefo're for making pulverulent fungistatic prepera- It is also possible to dissolve .the benzimidazole compound in suitable organic solvents and to impregnate the already milled, finely powdered solid pulverulent extending agent with such a solution. Thereafter the solvent is removed by evaporation.

When preparing tables, pills, dragees, and the like orally eliective solid shaped preparations the commonly used diluting agents, binders, lubricants, and-the like areemployed, such as sugar, lactose, starch, bolus ,alba, as binders, gelatine, pectin, gum arabic, methyl cellulose, yeast extract, agar, tragacanth, and as lubricants talc, steuric acid, magnesium stearate, and others.

The following examplesserve to illustrate various preparations as they can be used with great advantage in human and animal therapy as autifungal agents and spasmolytic preparations. It is, of course, understood that the use of the new benzimidazole compounds is not limited to the preparations given hereinafter in the examples, but that they may be used in any other suitable form.

Example 15 A highly eltective solution to be topically applied as .fungistatic agent is obtained by dissolving 5 g. of the hydrochloride of l-p-chloro benzyl-Z-methyl benzimidaiole in 'ccfof hot 1,2-propylene glycol and filtering "the hot solution. On cooling, a stable solution of said salt is obtained. In place of Ll-propylene glycol there can be .used as solvent ethylene glycol or glycerol or ether polyhydric alcohols.

Example 16 ill/hen pouring the solution of the hydrochloride of l-p chlo'ro benzyl 2 methylbenzimidazole in 1,2-propylene glycol obtained according to Example 15 into an equal volume of water, a finely divided, stable suspension of said salt is obtained which is also useful for therapeutical purposes.

Example 17 5 g. of l-p-chloro benzyl-Z-methyl benzirnidazole are incorporated into an ointment composed of '10 g. of glycerol, 45 g. of Vaseline, and 40 g. of lanolin. The resulting ointment has proved of value as fungistatic ointment.

Example 18 An antifungal paste is obtained by admixing to the ointment obtained according to Example 16, about 100 g. of zinc oxide or talc.

Example 19 A solution of 6 g. of the hydrochloride of l-p-chloro benzyl-Z-methyl benzimidaz ole in 100 cc. of 1,2-propylene glycol is prepared and applied topically to areas of the skin infected by fungi.

Example 20 A solution of 10 g. of the salt of 1-p-chloro benzyl- Z-rnethyl benzimidazole with undecylenic acid in 100 cc. of 1,2-propyler1e glycol is prepared and therapeutically used as antifungal agent.

Example 21 An aqueous solution of the salt of 1-p-chloro benzyl- Z-methyl benzimidazole with lactic acid is obtained by heating 5.1 g. of l-p-chloro benzyl-Z-methyl benzimidazole in 9.5 cc. of water and adding thereto 1.8 g. oflactic acid. The cooled solution is useful in the treatment gara es Example 22 Gelatin capsules are filled with an intimate mixture of 100 mg. of the hydrochloride of l-p-chloro benzyl-2- methyl benzimidazole and 15 mg. of calcium phosphate. One gelatin capsule represents the preferred single dose to be orally administered.

Example 23 Tablets are prepared from a mixture of 100 mg. of l-p-chloro benzyl-Z-methyl benzimidazole, 300 mg. of starch,

100 mg. of calcium phosphate, and

5 mg. of magnesium stearate.

The tablets can be administered orally as spasmolytic agents. Apparently they also possess an antifungal effect on such oral administration.

When using the new benzimidazole compounds as spasmolytic agents, the maximum single dose is about 250 mg. and the maximum daily dose is about 1000 mg. The preferred dosage is between about 50 mg. and about 150 mg. The preparations according to the present invention have proved to be especially effective in relieving spasms of the gastro-intestinal tract including the biliary tract.

For the prevention and treatment of fungus infections of the skin the new compounds are topically applied after the affected part has been thoroughly cleaned. Preferably the powder is applied during the day and the ointment, cream and the like preparation during the night. The powder may be dusted into the shoes and stockings for the control of susceptible fungus infections involving the feet.

Of course, many changes and variations in the manner in which the new benzimidazole compounds are prepared, the starting materials used, the solvents employed, the reaction conditions, temperature, and duration, the methods of isolating and purifying the resulting reaction products, the manner in which the new benzimidazole compounds are administered as spasmolytic agents and for combating fungus infections, and the like may be made by those skilled in the art in accordance with the principles set forth herein and in the claims annexed hereto.

We claim:

1. l-p-chloro benzyl-Z-methyl benzimidazole.

2. The hydrochloride of l-p-chloro benzyl-2-methyl benzimidazole.

3. The hydrate of l-p-chloro benzyl-Z-methyl benzimidazole.

4. The sulfate of l-p-chloro benzyl-Z-methyl benzimidazole.

5. The phosphate of l-p-chloro benzyl-Z-methyl benzimidazole.

6. The substantiallly non-toxic acid addition salts of l-p-chloro benzyl-Z-rnethyl benzimidazole with mineral acids.

7. The benzimidazole compound selected from the group consisting of the benzimidazole compound of the formula C Hz -X wherein X indicates a member selected from the group consisting of chlorine, bromine, and iodine, and its substantially non-toxic addition salts with acids having substantially no therapeutic activity.

References Cited in the file of this patent UNITED STATES PATENTS 2,312,923 Martin et a1. Mar. 2, 1943 2,689,853 Schenck et al Sept. 21, 1954 2,728,776 Schenck Dec. 27, 1955 FOREIGN PATENTS 1,084,467 France July 7, 1954 895,904 Germany Aug. 30, 1954 901,649 Germany Aug. 30, 1954 911,261 Germany Aug. 30, 1954 927,993 Germany May 23, 1955 295,243 Switzerland Feb. 16, 1954 300,469 Switzerland Oct. 1, 1954 

7. THE BENZIMIDAZOLE COMPOUND SELECTED FROM THE GROUP CONSISTING OF THE BENZIMIDAZOLE COMPOUND OF THE FORMULA 